Melatonin in PCO

 

The bottom line is we still do not have sufficient research works or  lab evidence to deficiency of Melatonin in PCO women

 

Melatonin is an old and ubiquitous molecule in nature showing multiple mechanisms of action and functions in practically every living organism. In mammals, pineal melatonin functions as a hormone and a chronobiotic, playing a major role in the regulation of the circadian temporal internal order. The anti-oestrogen and the weight-reducing effects of melatonin depend on several mechanisms and actions. Experimental evidence demonstrates that melatonin is necessary for the proper synthesis, secretion, and action of insulin. Melatonin acts by regulating GLUT4 expression and/or triggering, via its G-protein-coupled membrane receptors, the phosphorylation of the insulin receptor and its intracellular substrates mobilizing the insulin-signaling pathway. Melatonin is powerful chronobiotic being responsible, in part, by the daily distribution of metabolic processes so that the activity/feeding phase of the day is associated with high insulin sensitivity, and the rest/fasting is synchronized to the insulin-resistant metabolic phase of the day. Furthermore, melatonin is responsible for the establishment of an adequate energy balance mainly by regulating energy balance mainly by regulating energy  flow to and from the stores and directly regulating the energy expenditure through the activation of brown adipose tissue and participating in the browning process of white adipose tissue. The reduction in melatonin production, as during aging, shift-work or illuminated environments during the night, induces insulin resistance, glucose intolerance, sleep disturbance, and metabolic circadian disorganization characterizing a stats of chronodistruption leading to obesity. The available evidence supports the suggestion that melatonin replacement therapy might contribute to restore a more healthy state of the organism.

Point-counterpoint evaluation of supplementing Melatonin in PCO .

Melatonin is the key mediator molecule for the integration between the cyclic environment and the circadian distribution of physiological and behavioral processes and for the optimization of energy balance and body weight regulation events that are crucial for a healthy metabolism.

There are data confirming that melatonin regulates other aspects of adipocytes biology that influence energy metabolism lipidemia and body weight as lipolysis lipogenesis, adipocyte differentiation and fatty acids uptake among others.

Another major site o melatonin’s action in reference to the regulation of energy metabolism is the pancreatic islets where if influences insulin and glucagon synthesis and release. MTI and/or MT2 mediated action decreases glucose stimulated insulin secretion in isolated rat pancreatic islets and rat insulinoma beta cells.

As a consequence melatonin is fundamental for the maintenance of the internal circadian temporal organization timing many physiological processed including energy metabolism and their synchronization which is crucial for health maintenance.

There are consistent experimental data showing that the absence of melatonin cycle in the blood of pinealectomized animals impairs the temporal organization and circadian distribution of several metabolic functions associated with energy metabolism such as daily insulin secretion, glucose tolerance and insulin sensitivity, metabolic adaptations to activity /feeding and rest /fasting and daily distribution of glycogen synthesis and lipogenesis as opposite to those of glycogenolysis  and lipolysis .

The postulated anti obesogenic effect of melatonin is in part a result of its regulatory role on the balance of energy acting mainly on the regulation of the energy flux to and from the stores and in energy expenditure . Moreover its association with all the physiological processes typical of the daily activity wakefulness/rest sleep rhythm may impact body weight.

In summary it seems that the adequate supplementation of melatonin lowers body weight and body weight gain as well as the intra abdominal visceral fat deposition. This might be the result of the re establishment of the circadian distribution of energy metabolism the recovery of insulin signaling the consequent disappearance of insulin resistance and glucose intolerance and most importantly the accentuation of the energy expenditure over the energy intake resulting in weight loss and stabilization of weight gain.

Concluding Remarks

Melatonin is the key mediator molecule in the integration between the cyclic environment and the circadian distribution of physiological and behavioral processes necessary for a healthy metabolism and for the optimization of energy balance and body weight regulation. Melatonin acts by potentiating central and peripheral insulin action either due to regulation of GLUT4 expression or triggering the insulin signaling pathway. Thus it induces via its G protein coupled membrane receptors the phosphorylation of the insulin receptor and its intracellular substrates. Melatonin is a powerful chronobiotic influencing among others the circadian distribution of metabolic processes synchronizing them to the activity feeding /rest fasting cycle. Melatonin is responsible for the establishment of an adequate energy balance mainly by regulating the energy flow to and from the stores and directly regulating the energy expenditure through the activation of brown adipose tissue. Additionally melatonin causes the browning of the white adipose tissue thereby aiding in regulating body weight. The absence or reduction in melatonin production as during the night induces insulin resistance glucose intolerance sleep disturbance and metabolic circadian disorganization characterizing a state of chronodistruption and metabolic diseases that constitute a vicious cycle aggravating overall health and leading of obesity. The available evidence supports the suggestion that melatonin replacement therapy if adequately carried out might prevent and/or contribute to the elimination of the above pathologies and restore a more healthy state to the organism.

Introduction

Melatonin is an ancient molecule ubiquitously present in nature including both ;plant ad animals . Ii is well known that in mammals melatonin is synthesized in several cells tissues and organs mainly for local utilization and that circulating melatonin is largely provided by the pineal gland where it is produced and directly released to the blood and cerebrospinal fluid. 

While pineal melatonin has all the characteristics of a hormone it also has features which distinguish it from classical hormones. It is centrally produced in an endocrine gland circulates in a free and albumin linked form and can act through specific G protein coupled membrane receptors  as well as on putative nuclear RZR/ROR retinoid receptors. Melatonin’s membrane receptor-mediated mechanisms of action and its physiological effects via those receptors have been defined . Conversely its mechanisms of action at the nuclear level are less well defined . Melatonin’s direct free radical scavenging actions account for its receptor independent effects.

Pineal melatonin production is under control of the par ventricular nucleus of the hypothalamus which project eventually to the intermediolateral column of the upper thoracic segments of the spinal cord where the sympathetic preganglionic neurons are located. The axons of these neurons exit the cord and pass to the rostral third of the superior cervical ganglia which in turn send postganglionic sympathetic projections through the coronary  nerves to the pineal gland. Norepinephrine is released from these nerve endings where it interacts with and postsynaptic adrenoreceptors  to trigger several intracellular transduction mechanisms that activate melatonin synthesis in the pinealocytes.

The activation /deactivation of this complex neural path way controlling pineal  melatonin synthesis is under the precise control of the master circadian clock the suprachiasmatic nucleus of the hypothalamus . Via this pathway melatonin production expresses a circadian rhythm that is tightly synchronized to the light /dark cycle. The circadian control is such that melatonin production is always circumscribed to the night regardless the behavioral distribution  of activity and rest of the considered mammalian species that is it is considered the chemical expression of darkness . Moreover high production is maintained during the dark phase of the light/ dark cycle provided there is no light in the environment as light during the night blocks melatonin production . These functional particularities of the mammalian system that control pineal melatonin production guarantee that the circadian clock triggers melatonin production daily at night and that environmental light and the clock determine the duration of the daily episode of melatonin synthesis . In this way given the adequate ecological and social habitat conditions , the physiological system that controls melatonin synthesis allows the nocturnal profile of circulating melatonin to vary according to the duration of the daily scot period reflecting therefore the season of the year and acting as a neuroendocrine mediator of the photoperiod . Because of this the circadian melatonin rhythm drives annual reproductive and metabolic cycles in photoperiod sensitive mammals. In part due to the above chronobiological characteristics of production melatonin is one of the main mediators used by the central master clock to time central and peripheral tissues acting  as an internal synchronizer or internal zeitgeber. Moreover melatonin is able to act on peripheral oscillators regulating their phase and period mainly by controlling the transcription/translation circadian cycle of the peripheral clock genes . This functional aspect makes melatonin one of the most important chronobiotic that directly participates in the organization of the circadian temporal coordination of physiological and behavioral phenomena.